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Inhibition of #-amyloid Channels with a Drug Candidate wgx-50 Revealed by Molecular Dynamics Simulations Shuang Hou, RUO-XU GU, and Dong-Qing Wei J. Chem. Inf. Model., Just Accepted Manuscript • DOI: 10.1021/acs.jcim.7b00452 • Publication Date (Web): 03 Nov 2017 Downloaded from http://pubs.acs.org on November 4, 2017

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Journal of Chemical Information and Modeling

Inhibition of β-amyloid Channels with a Drug Candidate wgx-50 Revealed by Molecular Dynamics Simulations Shuang Hou1, Ruo-Xu Gu2*, Dong-Qing Wei1*

1

State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology,

Shanghai Jiao Tong University, Shanghai 200240, China 2

Department of Biological Sciences and Centre for Molecular Simulation, University of Calgary,

2500 University Dr. N.W., Calgary, AB, T2N 1N4, Canada

Corresponding authors: [email protected], [email protected]

Keywords: Alzheimer’s disease, β-amyloid ion channels, Ca2+ leaking, ion conductance, molecular dynamics simulation

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ABSTRACT Destabilization of cellular ionic homeostasis by toxic β-amyloid (Aβ) channels/barrels, which is a pathogenic mechanism for Alzheimer’s disease (AD), is inhibited by a novel anti-AD drug candidate wgx-50 significantly in our previous biological experiments. In this work, molecular dynamics (MD) simulations are conducted to investigate wgx-50-Aβ channels/barrels interactions, as well as the ion conductance inhibition mechanism. Ion influx from extracellular side to the central pore, which is found in apo-form simulations, is blocked by wgx-50 ligands that bind to the hydrophobic rings at the entrance of the channels/barrels. WGX-50 binding results in smaller pore diameter of the channels/barrels, however the overall morphology of them remains unaffected in accessible simulation time. WGX-50 binding site in this work consists with what we found in our previous simulations of Aβ protofibril. Our work not only investigates the ligand-Aβ channels/barrels interaction mechanism, but also provides insights into rational drug design of Alzheimer’s disease.


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INTRODUCTION Abnormal protein aggregation is responsible for a variety of neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and type II diabetes.1-3 The AD is pathologically characterized by the deposition of insoluble senile plaques (SP) composed primarily of β-amyloid (Aβ) peptides that are generated by sequential cleavage of amyloid precursor protein (APP) by proteolytic enzymes (α, β, and γ-secretase) in the brain4. Although the exact pathogenic mechanism of AD is still not clear5, the insoluble fibril-like Aβ aggregations were considered to play a critical role. However, the emerging amyloid cascade hypothesis holds that soluble small Aβ oligomers, rather than the insoluble amyloid fibrils or plaques, are the predominant toxic species that can lead to sequential downstream reactions6, including injury to synapses and neurites of brain neurons, activation of microglia and astrocytes, alteration of neuronal ionic homeostasis and kinase/phosphatase activities, which ultimately result in dementia.7-12 The toxicity of Aβ oligomers is considered to be related with the disruption of the ionic homeostasis (particularly calcium).13 However, the mechanism of Aβ oligomers induced membrane permeability remains controversial, although a variety of hypotheses, from pure mechanical reasons to Aβ oligomer-ion channel interactions, have been proposed14. Among them, one well accepted theory is the amyloid ion channel hypothesis, which suggests that small Aβ oligomers insert into the membrane spontaneously and assemble to form channel like structures, which may destabilize the cellular ionic homeostasis through unregulated ionic flux.15-16 Evidences supporting this hypothesis involve both experiments and molecular dynamics (MD) simulations.17-21 Electrophysiological experiments using artificial constructed planar lipid bilayers have revealed ion conductance elicited 3 ACS Paragon Plus Environment


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by the Aβ channels with heterogeneous strength that fluctuates from 5 ps to 2 nS, due to their heterogeneous compositions/structures.17-18, 22 Ion conductance strength revealed by different groups are consistent with each other.17, 22 MD simualtions of Aβ channels were conducted to investigate the behaviors of different cations, such as Mg2+, Ca2+, Zn2+ and K+, and found that the cations were accumulated in the vicinity of Glu22 residues at the upper half potions of the central pore, creating a cationic ring.19, 23-28 The necessary concentrations of peptides that used in experiments of ion channel reconstitution to show physiological effects at cellular level vary significantly and a high concentration (micromolar) of peptides is usually required29. A variety of experimental techniques, including electron microscopy (EM)20, 30-31 and atomic force microscopy (AFM)18-19, 21, have been conducted to investigate the structure of the putative Aβ channels. Most of these studies revealed a β-sheet enriched structure, in which the Aβ peptides assemble to oligomers and these oligomers are then used as subunits to constitute an imperfect annual structure with a central pore. Two conformations are considered to be possible: the channel conformation, in which the Aβ monomers are arranged parallel to the axis of the central pore, and the barrel conformation, in which the β-strands have a tilt angle along the tangential direction of the central pore. Among them, the barrel conformation is more energetically favorable

17, 25-28, 32

. Since

atomistic details of their structures have not been available at present, extensive molecular dynamics (MD) simulations17, 19, 23-28, 32-33 are carried out to explore the detailed conformation and optimal size of the Aβ channels/barrels that embedded in membrane bilayer. In the MD simulations, the stable and functional Aβ channel/barrel conformation has a pore-preserving topology, and each monomer folds into the U-shaped β-strand-turn-β-strand motif with the hydrophilic N-terminal strands 4 ACS Paragon Plus Environment

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constituting the solvated pore and the hydrophobic C-terminal strands interfacing with the lipids. The most stable Aβ channels and barrels are 16-, 20-, and 24-mer oligomers, and 12-, 16-, and 20-mer oligomers, respectively, according to these simulations24-25 and AFM experiments

18-19, 21, 26-27

. It is

proposed that the dimensions of the Aβ channels/barrels should be in a range that allow the formation of inter-strand hydrogen bonds between both the N- and C-terminal parts of the β strands within the subunits, in order to maintain the oligomerization of these peptides and provide proper distance for the neighboring subunits to form hydrogen bonds between them and ensure the integrity of the whole channels/barrels. We would like to note that, although substantial evidences support the β-sheet enriched structure for the Aβ channels/barrels that mentioned above34, molecular modeling has constructed polymorphic pore like structures constituted by α helices or combination of helices and β sheets35, which cannot be ruled out before experimental structures available. It is essential to develop novel medications for the treatment of AD, because the current anti-AD drugs in the market, including the cholinesterase inhibitors (donepezil, reminyl, razadyne, and rivastigmine) and the N-methyl-D-aspartate (NMDA) receptor antagonist (memantine)14, are only effective for 6-12 months for the patients and fail to prevent the progression of AD.36 In this regard, the toxic Aβ channels/barrels can be used as potential drug targets and potent inhibitors have been developed. For example, MRS2481 and its enantiomer, MRS2485, were able to protect neurons from Aβ toxicity effectively by blocking the Aβ channel pore.37 Additionally, diazoxide, a potassium ATP channel activator, was reported to improve memory and reduce the accumulation of Aβ amyloids in the cortex and hippocampus in mouse model with AD in in vivo experiments by suppressing the depolarization effects of the Aβ channels on neurons.38 Isradipine, a voltage-gated 5 ACS Paragon Plus Environment


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calcium channel blocker, also hyperpolarized neuron membranes and exerted protective effects on cultured neurons from Aβ toxicity in in vitro experiments.39 In addition to the inhibitors mentioned above, a potent drug candidate for AD, known as the molecular wgx-50 (earlier as gx-50, N-[2-(3,4-dimethoxyphenyl)ethyl]-3-phenyl-acrylamide, Fig. 1) has been developed recently.40-44 A series of biological experiments41-44 were carried out to validate its therapeutic effects on AD: in vivo experiments, such as pharmacokinetic assay, cognitive abilities test, and immunohistochemical analysis of brain sections of transgenic mouse model, found that wgx-50 is able to pass through the blood brain barrier, improve the cognitive abilities of mice, and decrease the accumulation of Aβ oligomers in the cerebral cortex; in vitro experiments, including atomic force microscopy of Aβ oligomers, and cell apoptosis assays, proved that wgx-50 disassembles Aβ oligomers, inhibits Aβ-induced neuronal apoptosis, and has anti-inflammatory effects by counteracting Aβ-triggered microglial overactivation. Of particular interest, pretreatment of neurons by wgx-50 before adding Aβ amyloids significantly inhibits accumulation of Ca2+ at the cytoplasmic side,44 and reduces neuronal calcium toxicity, implying that wgx-50 inhibits Aβ peptide induced ion conductance. Our previous MD simulations45 found that wgx-50 can disrupt the Aβ protofibril structure by breaking the Asp23-Lys28 salt bridges located in the interior of the Aβ protofibrils and packing around the Ile32 and Leu34 residues, resulting in separation of the tightly compacted two β-sheets. In this work, we employed MD simulations to investigate the inhibitive effects of wgx-50 on the Aβ peptide induced transmembrane ion conductance. Our simulations are based on the well accepted hypothesis that the membrane leakage is ascribed to Aβ channels/barrels. We constructed Aβ 6 ACS Paragon Plus Environment

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channels/barrels with β-sheet enriched structures of different sizes and conducted simulations in the presence and absence of wgx-50 molecules, respectively, in order to investigate their conformations and interactions with wgx-50. The Aβ channels/barrels exist as assembles of subunits in the simulations, as indicated in literatures19, 23-27, 33. WGX-50 molecules accumulated at the entrance and exit of the channels/barrels by forming hydrophobic interactions, and hence the central pores were occluded and the ion conductance was inhibited. We also found that, the pore diameters were reduced in the presence of wgx-50, however, the collapse process of Aβ channels/barrels were not accessible in the current simulation time. Our work may provide atomistic details for the inhibition mechanism of Aβ channels/barrels by ligands, and give insights into rational drug design targeting these oligomers.



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METHODS Simulation systems. The Aβ channels/barrels were constructed based on the Aβ monomer with the U-shaped β-strand-turn-β-strand structure by rotating it multiple times to form oligomers with ideal annular shape. The Aβ monomers were parallel to the axis of the oligomer in the Aβ channels, whereas they had a tilt angle of ~37° relative to the central pore axis in the Aβ barrels (Fig. 2). The system setup in this work is consistent with protocols used in previous simulations.23-25 Three channels with 16, 20, and 24 monomers, and three barrels with 12, 16, and 20 monomers, which are considered as the most stable oligomers, were constructed respectively. We only built the pore-preserving CNpNC structure (C and N refer to the C- and N-terminal of the β-strands, respectively, and p refers to the central pore) in which the charged N-terminal β-strands enclose the central pore and the hydrophobic C-terminal β-strands interface with the lipid bilayer. In the initial constructed conformations, intermolecular hydrogen bonds were formed between the N-terminal β-strands, but not between the C-terminal β-strands due to larger curvature at the periphery. Structure of the initial Aβ monomer that used to constructed the channels/barrels was extracted from the solid-state NMR structure of Aβ17–42 pentamer46 (PDB ID: 2BEG). The Aβ monomer conformation, and example Aβ channels/barrels conformations are shown in Fig. 2. Each monomer is divided into three parts: pore-lining N-terminal β-strand, turn, and lipid-facing C-terminal β-strand. The pore-lining N-terminal section consists of two negatively charged residues (Glu22 and Asp23, shown in red in Fig. 2) and seven hydrophobic residues (Leu17, Val18, Phe19, Phe20, Ala21, Val24, Gly25, shown in white in Fig. 2); the turn comprises two polar residues (Ser26 and Asn27, shown in green in Fig. 2), one positively charged residue (Lys28, shown in blue in Fig. 2) and three hydrophobic 8 ACS Paragon Plus Environment

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residues (Gly29, Ala30, Ile31, shown in white in Fig. 2); and the C-terminal region only contains hydrophobic residues (Ile32, Gly33, Leu34, Met35, Val36, Gly37, Gly38, Val39, Val40, Ile41, Ala42, shown in white in Fig. 2). The Aβ channels/barrels were then inserted into the 2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) bilayer using CHARMM-GUI47 and subjected to molecular dynamics (MD) simulations. DOPC lipids were used in order to be consistent with experiments26-27. The bilayers are composed of ~200-400 lipids, depending on the sizes of the Aβ channels/barrels. Parallel simulations with and without wgx-50 molecules were performed for each Aβ channel/barrel, and twelve simulations were conducted in total. For the simulations with wgx-50, ten ligands were added to each system on both sides of the bilayers. Mg2+, K+, Ca2+, and Zn2+, each with a concentration of 25 mM, were added to explore ion conductance through the channels/barrels. Cl- ions with equivalent concentration were added to neutralize the system. We note that the concentrations of cations in simulations are different with the corresponding experimental values (e.g., concentration of Ca2+ in experiments is ~2 mM44). However, we are using higher concentrations in order to observe as many as ion translocation events in relatively short simulation time, and compare with simulations in literatures which applied the same ion concentration17, 19, 23-25, 27-28, 32. Each system (~ 12 nm × 12 nm × 10 nm in x, y, and z) contains 1 Aβ channel/barrel, ~200-400 DOPC lipids, 0 or 10 wgx-50 molecules, ~20,000-30,000 waters and ~40-64 ions in total. The exact compositions and sizes of the simulation systems are summarized in Table S1. Molecular dynamics simulation protocol. The MD simulations were conducted by GROMACS5 package48 using the CHARMM36 force field49 and the TIP3P water model50. Firstly, 9 ACS Paragon Plus Environment


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1000 steps energy minimization was conducted using the steep descent algorithm. Then we performed two 0.5 ns simulations with different force constants for position restraints using the NVP ensemble, followed by 0.5, 1.0, 1.0 and 2.0 ns simulations consecutively using the NPT ensemble to equilibrate the simulation system. Position restraints with force constants of 4000, 2000, 1000, 500, 200 and 50 kJ/(molnm2) were applied on the peptide backbone, respectively, for each part of the simulation. At last, we conducted 100 ns production simulations without any positions restraints using the NPT ensemble. Simulations of the 16-mer Aβ channel system were extended to 500 ns for better sampling. The temperature was maintained at 300 K using the Nose-Hoover thermostat51-52 and a relaxation time of 1 ps and the pressure at 1 bar for all three dimensions using the Parrinello-Rahman barstat53, the semi-isotropic coupling method with a relaxation time of 5 ps and a compressibility of 4.5 × 10−5 bar−1. The van der Waals interactions were turned off from 1.0 nm to 1.2 nm using the force based switch function54, whereas the long range electrostatic interactions were dealt with the Particle Mesh Ewald (PME) algorithm55. The simulation time step was set to 2 fs in conjunction with the LINCS algorithm56 to constrain the covalent bonds involving hydrogen atoms. Parameters of the wgx-50 molecule were from the CHARMM General Force Field (CGenFF) parameter set57-59, which strives to cover a wide range of chemical spaces and is used to build force field for drug-like molecules that compatible with the CHARMM force field of biomolecules. Fig. S1 shows the atom types and partial charges that used for wgx-50 molecule. Simulations using CGenFF parameters of wgx-50 in this work identified the same ligand binding site with our previous simulations45 (see the results sections), suggesting the reliability of the parameters.


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Analysis details. The last 50 ns and 200 ns trajectories were used for the analyses of the 100 ns and 500 ns simulations, respectively. The pore diameters and pore surface were calculated by the HOLE program60, whereas the outer diameters were obtained based on the cross-sectional areas that measured by the CHARMM package61, assuming that the cross sections were circles, which may result in slightly underestimated values. The pore and outer diameters were calculated for each frame in the trajectories, and the averages were reported. Morphology of the Aβ oligomers were characterized by multiple parameters including the β-strand order parameter (Sβ)19, 23-24, 26, 33, the percentage of β-sheet content, the averaged B factor of β-strand23-24, and the effective β-strand distance25. The β-strand order parameter (Sβ), which was used to measure the straightness of the β-strands, was defined as:

1 N  3 cos 2 θ α − 1  , Sβ = ∑  N k =1  2  where θα is the angle between the vectors that connecting two adjacent Cα atoms and N is the total number of vector pairs. Percentage of β-sheet content was calculated based on the intermolecular backbone hydrogen bonds between adjacent β-stands. The B-factor was calculated by the following equation: B = 8π2/3, in which RMSF was the root mean square fluctuation. The reported B factor was an average over all of the residues in the same β-strand. The effective β-strand distance (D*) was calculated by: D* =

1 , DCα



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where the brackets denoted the time average and DCα was the distance between two Cα atoms of the corresponding residues in neighboring β-strands. The secondary structure of the β-strands was determined by the Stride62 web service. To calculate the RMSD values of the peptides, the Aβ channels/barrels were superimposed to the initial conformation based on the backbone of the oligomers, and then the RMSD values of the C- and N-terminal and the turn parts of each peptides were calculated separately. The D23-K28 salt-bridge distances were defined as the distance between the center of mass (COM) of the Nζ-amino groups of Lys28 and the COM of the Cγ-carboxylates of Asp23. Hydrogen bonds are defined as follows: the distance between the heavy atoms is within 0.35 nm, and the hydrogen-donor-acceptor angle is within 30º. The interaction energies are calculated as a sum of the electrostatic interaction energies and the van der Waals interaction energies.


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RESULTS AND DISCUSSION Six Aβ channels/barrels in ideal annual shape are constructed and subjected to MD simulations with and without wgx-50 molecules to investigate the effects of ligands on their conformation and ion conductance. Our simulations reveal differences in the pore diameter and ion distribution along the central pore of the channels/barrels between the apo-forms and wgx-50 binding forms, and suggest possible ligand-oligomer interaction mechanism and inhibition mechanism of ion conductance through the Aβ channels/barrels by small molecules. Conformation of Aβ channels/barrels in the absence of WGX-50. Consistent with previous studies17, 19, 23-28, 32-33, the initial ideal annual morphology of the Aβ channels/barrels is disrupted in the simulations. The Aβ oligomers are reorganized to several subunits that constituted by variable number of peptides via breaking and formation of intermolecular hydrogen bonds between the peptides. The boundaries of these subunits are defined by the broken of the hydrogen bonds between the Aβ peptides. As shown in Fig. S2 (results of 20-mer channel are used as an example), the numbers of hydrogen bonds formed between peptides at subunit boundaries decrease from ~10 to ~4 as the simulation time evolve, whereas the hydrogen bond numbers of the peptides that constituting the subunits are ~15-18 after equilibration. The central pore of the oligomer is surrounded by the N-terminal parts of the β-strands in the subunits and the disordered peptides in between them. The C-terminal parts of the peptides, which do not form β-sheets in the initial structure, regain intermolecular hydrogen bonds and β-sheet structure to some extent in the simulations.



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The morphology described above is characterized by the Sβ, percentage of β-sheet contents, averaged B-factor and effective distance between peptides (D*), which are calculated for the N- (res. 17-25) and C-terminal (res. 32-42) part of the peptides separately. Briefly, the β-strands constituting the subunits are more organized and therefore have larger Sβ values, higher percentage of β-sheet content, smaller B-factor, and larger D* values, compared with the disordered Aβ monomers in between them. The same trends are observed for both the N- and C-terminal part, although the C-terminal strands are more disordered than the N-terminal strands. Results of the 20-mer channel simulation are described below as an example (Fig. 3). Three subunits composed of 2, 6, 9 β-strands (constituted by peptides 1-2, peptides 4-9, and peptides 12-20, respectively, shown in green, red and blue in Fig. 3D) were found in the 20-mer channel simulation. The Sβ, percentage of β-sheet content, B factor, and effective distance of the N-terminal parts of the peptides in these subunits are >0.7, >60%, 1.5, respectively, significantly different with the corresponding values of the disordered monomers in between them, which are

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